Therapeutics: Proteasome subunit β2 (PSMB2)

In vitro and mouse studies identified a PSMB2 inhibitor that could help treat cancer. Chemical synthesis and in vitro testing of quinoline-sulfonyl analogs identified a compound (VR23) that inhibited PSMB2 in multiple proteasomes with IC50 values of 1-50 nM. In human MM cell lines, including lines resistant to Velcade bortezomib, VR23 inhibited growth at IC50 values of 1.0-3.0 μM and VR23 plus Velcade decreased growth synergistically compared with either agent alone. In a xenograft mouse model of MM, VR23 decreased tumor growth compared with vehicle. In a xenograft mouse model of breast cancer, VR23 plus the generic chemotherapy paclitaxel decreased tumor growth compared with paclitaxel alone. In normal mice, VR23 plus paclitaxel exhibited less liver, spleen and kidney toxicity than paclitaxel alone. Next steps in collaboration with Ramsey Lake Pharma Corp. include testing VR23 in models of other cancers...